Project Summary/Abstract Project 3. User-control and safety. A major feature of cell therapies that gives them their unique power is their ability to autonomously execute critical microscopic tasks within the body. But these properties also make the cells notoriously difficult to control once they are in the body ? if anything goes wrong it can be very difficult for the physician to communicate with the cells and provide new, specific instructions, aside from relatively crude kill-switches. For these reasons, it is critical to develop new communication channels that can be used to mediate user-control of the engineered cells. Here we are focused on developing two platforms for user-control: engineering immune cells so that their activity is gated by FDA approved drugs, or by bio-compatible nano/micromaterials. Our aims are: 1) develop ways to use FDA approved small molecule drugs to control both CARs and SynNotch receptor activities; test their ability to control engineered cell function in vivo. 2) develop new biocompatible modular microparticle platform that can be flexibly engineered to display combinatorial molecular instructions for therapeutic cells. 3) Use this microparticle platform to control priming and activation of engineered therapeutic cells in vivo. 4) Use this microparticle platform as way to optimize ex vivo and in vivo and expansion of therapeutic cells. The small molecule and microparticle platforms that we develop should provide flexible and precise ways to communicate with and control the activity of therapeutic cells in vivo, a critical way to improve safety of these therapies, as well as to optimize the location, amplitude and time of their activities.